Type 2 diabetes mellitus is a devastating disease placing afflicted individuals at the same risk for life threatening cardiovascular disease events (CVD) as those with diagnosed CVD. The public health burden attributed to this disease of insulin resistance and disrupted fatty acid balance has been burgeoning as rates of overweight and obesity have become epidemic in adults and children in the US and globally. Lifestyle and public policy approaches are necessary but not sufficient alone for the prevention and treatment of insulin resistance/type 2 diabetes and thus novel, safe, effective, and inexpensive therapies are needed to reduce the high risk of CVD in those affected with diabetes. The potential benefits of combining inexpensive over-the- counter aspirin and fish oil-derived omega-3 fatty acids (eicosapentaenoic acid {EPA} and docosahexaenoic acid {DHA};"EPA+DHA") in the treatment and prevention of diabetes have not received much attention despite the robust cardioprotective effects demonstrated for both in a variety of other populations. A paradox exists as, although aspirin has robust platelet inhibitory effects, new evidence suggests that it does not reduce rates of CVD events in individuals with type 2 diabetes without a history of a CVD clinical event. The lack of effect of aspirin in the prevention of CVD has been termed "aspirin resistance" with those affected at substantially increased risk of CVD events compared to those who respond normally to aspirin. These facts do not warrant an abandonment of aspirin therapy for the primary prevention of CVD in diabetic individuals. Instead, investigations into the etiology of aspirin resistance and means of overcoming it should ensue. Thus, investigating the ability of EPA+DHA to improve the benefits of aspirin on platelet function in diabetic individuals may hold promise for understanding if combination therapy can overcome aspirin resistance and reduce CVD events. Circulating EPA and DHA are contained largely in lysophospholipids, which contain a three-carbon backbone and variable fatty acyl side chains. In Preliminary Data, we show that both aspirin ingestion and EPA+DHA supplementation alter lysophospholipid metabolism using novel quantitative assays of different molecular species. Lysophospholipids including lysophosphatidylcholine (LPC) and lysophosphatidic acid (LPA) are now known to bind specific G-protein coupled receptors, which are being explored as novel therapeutic targets in cardiovascular and other diseases. Investigating the relationships between LPC and LPA metabolism, aspirin ingestion, and human atherosclerosis may lead to novel and effective approaches to overcoming aspirin resistance and reducing CVD events in individuals with diabetes. In the proposed study, we will investigate the effects of combining aspirin with EPA+DHA supplementation on platelet function and lysophospholipid metabolism in a clinical trial of individuals with type 2 diabetes mellitus. This trial will build on existing infrastructure in clinical and translational research, as well as our Preliminary Data using novel in- house assays. PUBLIC HEALTH RELEVANCE: The prevalence of type 2 diabetes mellitus is rapidly increasing in the US and globally due to the epidemic of overweight and obesity. Although public health policy and lifestyle approaches to prevent diabetes and its cardiovascular disease sequelae can be useful, novel, safe, effective, and inexpensive therapeutics are needed to help insulin resistant individuals live longer and healthier lives. This project will investigate the role of combined aspirin and fish-derived omega-3 fatty acid ingestion on platelet function while exploring how lysophospholipid metabolism is affected by the ingestion of these agents and associated with platelet function.